Cerebellar Functions Beyond Movement and Learning.

The cerebellum has a well-established role in controlling motor functions, including coordination, posture, and the learning of skilled movements. The mechanisms for how it carries out motor behavior remain under intense investigation. Interestingly though, in recent years the mechanisms of cerebellar function have faced additional scrutiny since nonmotor behaviors may also be controlled by the cerebellum. With such complexity arising, there is now a pressing need to better understand how cerebellar structure, function, and behavior intersect to influence behaviors that are dynamically called upon as an animal experiences its environment. Here, we discuss recent experimental work that frames possible neural mechanisms for how the cerebellum shapes disparate behaviors and why its dysfunction is catastrophic in hereditary and acquired conditions-both motor and nonmotor. For these reasons, the cerebellum might be the ideal therapeutic target.

The cerebellum contributes to generalized seizures by altering activity in the ventral posteromedial nucleus.

Thalamo-cortical networks are central to seizures, yet it is unclear how these circuits initiate seizures. We test whether a facial region of the thalamus, the ventral posteromedial nucleus (VPM), is a source of generalized, convulsive motor seizures and if convergent VPM input drives the behavior. To address this question, we devise an in vivo optogenetic mouse model to elicit convulsive motor seizures by driving these inputs and perform single-unit recordings during awake, convulsive seizures to define the local activity of thalamic neurons before, during, and after seizure onset. We find dynamic activity with biphasic properties, raising the possibility that heterogenous activity promotes seizures. Virus tracing identifies cerebellar and cerebral cortical afferents as robust contributors to the seizures. Of these inputs, only microinfusion of lidocaine into the cerebellar nuclei blocks seizure initiation. Our data reveal the VPM as a source of generalized convulsive seizures, with cerebellar input providing critical signals.

Breathing in waves: Understanding respiratory-brain coupling as a gradient of predictive oscillations.

Breathing plays a crucial role in shaping perceptual and cognitive processes by regulating the strength and synchronisation of neural oscillations. Numerous studies have demonstrated that respiratory rhythms govern a wide range of behavioural effects across cognitive, affective, and perceptual domains. Additionally, respiratory-modulated brain oscillations have been observed in various mammalian models and across diverse frequency spectra. However, a comprehensive framework to elucidate these disparate phenomena remains elusive. In this review, we synthesise existing findings to propose a neural gradient of respiratory-modulated brain oscillations and examine recent computational models of neural oscillations to map this gradient onto a hierarchical cascade of precision-weighted prediction errors. By deciphering the computational mechanisms underlying respiratory control of these processes, we can potentially uncover new pathways for understanding the link between respiratory-brain coupling and psychiatric disorders.

Cerebellar control of thalamocortical circuits for cognitive function: A review of pathways and a proposed mechanism.

There is general agreement that cerebrocerebellar interactions via cerebellothalamocortical pathways are essential for a cerebellar cognitive and motor functions. Cerebellothalamic projections were long believed target mainly the ventral lateral (VL) and part of the ventral anterior (VA) nuclei, which project to cortical motor and premotor areas. Here we review new insights from detailed tracing studies, which show that projections from the cerebellum to the thalamus are widespread and reach almost every thalamic subnucleus, including nuclei involved in cognitive functions. These new insights into cerebellothalamic pathways beyond the motor thalamus are consistent with the increasing evidence of cerebellar cognitive function. However, the function of cerebellothalamic pathways and how they are involved in the various motor and cognitive functions of the cerebellum is still unknown. We briefly review literature on the role of the thalamus in coordinating the coherence of neuronal oscillations in the neocortex. The coherence of oscillations, which measures the stability of the phase relationship between two oscillations of the same frequency, is considered an indicator of increased functional connectivity between two structures showing coherent oscillations. Through thalamocortical interactions coherence patterns dynamically create and dissolve functional cerebral cortical networks in a task dependent manner. Finally, we review evidence for an involvement of the cerebellum in coordinating coherence of oscillations between cerebral cortical structures. We conclude that cerebellothalamic pathways provide the necessary anatomical substrate for a proposed role of the cerebellum in coordinating neuronal communication between cerebral cortical areas by coordinating the coherence of oscillations.

"The great mixing machine": multisensory integration and brain-breath coupling in the cerebral cortex.

It is common to distinguish between "holist" and "reductionist" views of brain function, where the former envisions the brain as functioning as an indivisible unit and the latter as a collection of distinct units that serve different functions. Opposing reductionism, a number of researchers have pointed out that cortical network architecture does not respect functional boundaries, and the neuroanatomist V. Braitenberg proposed to understand the cerebral cortex as a "great mixing machine" of neuronal activity from sensory inputs, motor commands, and intrinsically generated processes. In this paper, we offer a contextualization of Braitenberg's point, and we review evidence for the interactions of neuronal activity from multiple sensory inputs and intrinsic neuronal processes in the cerebral cortex. We focus on new insights from studies on audiovisual interactions and on the influence of respiration on brain functions, which do not seem to align well with "reductionist" views of areal functional boundaries. Instead, they indicate that functional boundaries are fuzzy and context dependent. In addition, we discuss the relevance of the influence of sensory, proprioceptive, and interoceptive signals on cortical activity for understanding brain-body interactions, highlight some of the consequences of these new insights for debates on embodied cognition, and offer some suggestions for future studies.

Respiratory rhythms of the predictive mind.

Respiratory rhythms sustain biological life, governing the homeostatic exchange of oxygen and carbon dioxide. Until recently, however, the influence of breathing on the brain has largely been overlooked. Yet new evidence demonstrates that the act of breathing exerts a substantive, rhythmic influence on perception, emotion, and cognition, largely through the direct modulation of neural oscillations. Here, we synthesize these findings to motivate a new predictive coding model of respiratory brain coupling, in which breathing rhythmically modulates both local and global neural gain, to optimize cognitive and affective processing. Our model further explains how respiratory rhythms interact with the topology of the functional connectome, and we highlight key implications for the computational psychiatry of disordered respiratory and interoceptive inference. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Recent insights into respiratory modulation of brain activity offer new perspectives on cognition and emotion.

Over the past six years, a rapidly growing number of studies have shown that respiration exerts a significant influence on sensory, affective, and cognitive processes. At the same time, an increasing amount of experimental evidence indicates that this influence occurs via modulation of neural oscillations and their synchronization between brain areas. In this article, we review the relevant findings and discuss whether they might inform our understanding of a variety of disorders that have been associated with abnormal patterns of respiration. We review literature on the role of respiration in chronic obstructive pulmonary disease (COPD), anxiety (panic attacks), and autism spectrum disorder (ASD), and we conclude that the new insights into respiratory modulation of neuronal activity may help understand the relationship between respiratory abnormalities and cognitive and affective deficits.

Causal Evidence for a Role of Cerebellar Lobulus Simplex in Prefrontal-Hippocampal Interaction in Spatial Working Memory Decision-Making.

Spatial working memory (SWM) is a cerebrocerebellar cognitive skill supporting survival-relevant behaviors, such as optimizing foraging behavior by remembering recent routes and visited sites. It is known that SWM decision-making in rodents requires the medial prefrontal cortex (mPFC) and dorsal hippocampus. The decision process in SWM tasks carries a specific electrophysiological signature of a brief, decision-related increase in neuronal communication in the form of an increase in the coherence of neuronal theta oscillations (4-12 Hz) between the mPFC and dorsal hippocampus, a finding we replicated here during spontaneous exploration of a plus maze in freely moving mice. We further evaluated SWM decision-related coherence changes within frequency bands above theta. Decision-related coherence increases occurred in seven frequency bands between 4 and 200 Hz and decision-outcome-related differences in coherence modulation occurred within the beta and gamma frequency bands and in higher frequency oscillations up to 130 Hz. With recent evidence that Purkinje cells in the cerebellar lobulus simplex (LS) represent information about the phase and phase differences of gamma oscillations in the mPFC and dorsal hippocampus, we hypothesized that LS might be involved in the modulation of mPFC-hippocampal gamma coherence. We show that optical stimulation of LS significantly impairs SWM performance and decision-related mPFC-dCA1 coherence modulation, providing causal evidence for an involvement of cerebellar LS in SWM decision-making at the behavioral and neuronal level. Our findings suggest that the cerebellum might contribute to SWM decision-making by optimizing the decision-related modulation of mPFC-dCA1 coherence.

Conditional loss of Engrailed1/2 in Atoh1-derived excitatory cerebellar nuclear neurons impairs eupneic respiration in mice.

Evidence for a cerebellar role during cardiopulmonary challenges has long been established, but studies of cerebellar involvement in eupneic breathing have been inconclusive. Here we investigated temporal aspects of eupneic respiration in the Atoh1-En1/2 mouse model of cerebellar neuropathology. Atoh1-En1/2 conditional knockout mice have conditional loss of the developmental patterning genes Engrailed1 and 2 in excitatory cerebellar nuclear neurons, which leads to loss of a subset of medial and intermediate excitatory cerebellar nuclear neurons. A sample of three Atoh1-derived extracerebellar nuclei showed no cell loss in the conditional knockout compared to control mice. We measured eupneic respiration in mutant animals and control littermates using whole-body unrestrained plethysmography and compared the average respiratory rate, coefficient of variation, and the CV2, a measure of intrinsic rhythmicity. Linear regression analyses revealed that Atoh1-En1/2 conditional knockouts have decreased overall variability (p = 0.021; b = -0.045) and increased intrinsic rhythmicity compared to their control littermates (p < 0.001; b = -0.037), but we found no effect of genotype on average respiratory rate (p = 0.064). Analysis also revealed modestly decreased respiratory rates (p = 0.025; b = -0.82), increased coefficient of variation (p = 0.0036; b = 0.060), and increased CV2 in female animals, independent of genotype (p = 0.024; b = 0.026). These results suggest a cerebellar involvement in eupneic breathing by controlling rhythmicity. We argue that the cerebellar involvement in controlling the CV2 of respiration is indicative of an involvement of coordinating respiration with other orofacial rhythms, such as swallowing.

Cerebellar Coordination of Neuronal Communication in Cerebral Cortex.

Cognitive processes involve precisely coordinated neuronal communications between multiple cerebral cortical structures in a task specific manner. Rich new evidence now implicates the cerebellum in cognitive functions. There is general agreement that cerebellar cognitive function involves interactions between the cerebellum and cerebral cortical association areas. Traditional views assume reciprocal interactions between one cerebellar and one cerebral cortical site, via closed-loop connections. We offer evidence supporting a new perspective that assigns the cerebellum the role of a coordinator of communication. We propose that the cerebellum participates in cognitive function by modulating the coherence of neuronal oscillations to optimize communications between multiple cortical structures in a task specific manner.

Loss of cerebellar function selectively affects intrinsic rhythmicity of eupneic breathing.

Respiration is controlled by central pattern generating circuits in the brain stem, whose activity can be modulated by inputs from other brain areas to adapt respiration to autonomic and behavioral demands. The cerebellum is known to be part of the neuronal circuitry activated during respiratory challenges, such as hunger for air, but has not been found to be involved in the control of spontaneous, unobstructed breathing (eupnea). Here we applied a measure of intrinsic rhythmicity, the CV2, which evaluates the similarity of subsequent intervals and is thus sensitive to changes in rhythmicity at the temporal resolution of individual respiratory intervals. The variability of intrinsic respiratory rhythmicity was reduced in a mouse model of cerebellar ataxia compared to their healthy littermates. Irrespective of that difference, the average respiratory rate and the average coefficient of variation (CV) were comparable between healthy and ataxic mice. We argue that these findings are consistent with a proposed role of the cerebellum in modulating the duration of individual respiratory intervals, which could serve the purpose of coordinating respiration with other rhythmic orofacial movements, such as fluid licking and swallowing.

Consensus Paper: Experimental Neurostimulation of the Cerebellum.

The cerebellum is best known for its role in controlling motor behaviors. However, recent work supports the view that it also influences non-motor behaviors. The contribution of the cerebellum towards different brain functions is underscored by its involvement in a diverse and increasing number of neurological and neuropsychiatric conditions including ataxia, dystonia, essential tremor, Parkinson's disease (PD), epilepsy, stroke, multiple sclerosis, autism spectrum disorders, dyslexia, attention deficit hyperactivity disorder (ADHD), and schizophrenia. Although there are no cures for these conditions, cerebellar stimulation is quickly gaining attention for symptomatic alleviation, as cerebellar circuitry has arisen as a promising target for invasive and non-invasive neuromodulation. This consensus paper brings together experts from the fields of neurophysiology, neurology, and neurosurgery to discuss recent efforts in using the cerebellum as a therapeutic intervention. We report on the most advanced techniques for manipulating cerebellar circuits in humans and animal models and define key hurdles and questions for moving forward.

The rhythm of memory: how breathing shapes memory function.

The mammalian olfactory bulb displays a prominent respiratory rhythm, which is linked to the sniff cycle and is driven by sensory input from olfactory receptors in the nasal sensory epithelium. In rats and mice, respiratory frequencies occupy the same band as the hippocampal θ-rhythm, which has been shown to be a key player in memory processes. Hippocampal and olfactory bulb rhythms were previously found to be uncorrelated except in specific odor-contingency learning circumstances. However, many recent electrophysiological studies in both rodents and humans reveal a surprising cycle-by-cycle influence of nasal respiration on neuronal activity throughout much of the cerebral cortex beyond the olfactory system, including the prefrontal cortex, hippocampus, and subcortical structures. In addition, respiratory phase has been shown to influence higher-frequency oscillations associated with cognitive functions, including attention and memory, such as the power of γ-rhythms and the timing of hippocampal sharp wave ripples. These new findings support respiration's role in cognitive function, which is supported by studies in human subjects, in which nasal respiration has been linked to memory processes. Here, we review recent reports from human and rodent experiments that link respiration to the modulation of memory function and the neurophysiological processes involved in memory in rodents and humans. We argue that respiratory influence on the neuronal activity of two key memory structures, the hippocampus and prefrontal cortex, provides a potential neuronal mechanism behind respiratory modulation of memory.

Cerebellar Lobulus Simplex and Crus I Differentially Represent Phase and Phase Difference of Prefrontal Cortical and Hippocampal Oscillations.

The cerebellum has long been implicated in tasks involving precise temporal control, especially in the coordination of movements. Here we asked whether the cerebellum represents temporal aspects of oscillatory neuronal activity, measured as instantaneous phase and difference between instantaneous phases of oscillations in two cerebral cortical areas involved in cognitive function. We simultaneously recorded Purkinje cell (PC) single-unit spike activity in cerebellar lobulus simplex (LS) and Crus I and local field potential (LFP) activity in the medial prefrontal cortex (mPFC) and dorsal hippocampus CA1 region (dCA1). Purkinje cells in cerebellar LS and Crus I differentially represented specific phases and phase differences of mPFC and dCA1 LFP oscillations in a frequency-specific manner, suggesting a site- and frequency-specific cerebellar representation of temporal aspects of neuronal oscillations in non-motor cerebral cortical areas. These findings suggest that cerebellar interactions with cerebral cortical areas involved in cognitive functions might involve temporal coordination of neuronal oscillations.

Emerging connections between cerebellar development, behaviour and complex brain disorders.

The human cerebellum has a protracted developmental timeline compared with the neocortex, expanding the window of vulnerability to neurological disorders. As the cerebellum is critical for motor behaviour, it is not surprising that most neurodevelopmental disorders share motor deficits as a common sequela. However, evidence gathered since the late 1980s suggests that the cerebellum is involved in motor and non-motor function, including cognition and emotion. More recently, evidence indicates that major neurodevelopmental disorders such as intellectual disability, autism spectrum disorder, attention-deficit hyperactivity disorder and Down syndrome have potential links to abnormal cerebellar development. Out of recent findings from clinical and preclinical studies, the concept of the 'cerebellar connectome' has emerged that can be used as a framework to link the role of cerebellar development to human behaviour, disease states and the design of better therapeutic strategies.

Lentiviral-mediated knock-down of GD3 synthase protects against MPTP-induced motor deficits and neurodegeneration.

Converging evidence demonstrates an important role for gangliosides in brain function and neurodegenerative diseases. Exogenous GM1 is broadly neuroprotective, including in rodent, feline, and primate models of Parkinson's disease, and has shown positive effects in clinical trials. We and others have shown that inhibition of the ganglioside biosynthetic enzyme GD3 synthase (GD3S) increases endogenous levels GM1 ganglioside. We recently reported that targeted deletion of St8sia1, the gene that codes for GD3S, prevents motor impairments and significantly attenuates neurodegeneration induced by 1-methy-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The current study investigated the effects of GD3S inhibition on the neurotoxicity and parkinsonism induced by MPTP. Mice were injected intrastriatally with a lentiviral-vector-mediated shRNA construct targeting GD3S (shGD3S) or a scrambled-sequence control (scrRNA). An MPTP regimen of 18 mg/kg x 5 days reduced tyrosine-hydroxylase-positive neurons in the substantia nigra pars compacta of scrRNA-treated mice by nearly two-thirds. In mice treated with shGD3S the MPTP-induced lesion was approximately half that size. MPTP induced bradykinesia and deficits in fine motor skills in mice treated with scrRNA. These deficits were absent in shGD3S-treated mice. These results suggest that inhibition of GD3S protects against the nigrostriatal damage, bradykinesia, and fine-motor-skill deficits associated with MPTP administration.

Thalamocortical Communication in the Awake Mouse Visual System Involves Phase Synchronization and Rhythmic Spike Synchrony at High Gamma Frequencies.

In the neocortex, communication between neurons is heavily influenced by the activity of the surrounding network, with communication efficacy increasing when population patterns are oscillatory and coherent. Less is known about whether coherent oscillations are essential for conveyance of thalamic input to the neocortex in awake animals. Here we investigated whether visual-evoked oscillations and spikes in the primary visual cortex (V1) were aligned with those in the visual thalamus (dLGN). Using simultaneous recordings of visual-evoked activity in V1 and dLGN we demonstrate that thalamocortical communication involves synchronized local field potential oscillations in the high gamma range (50-90 Hz) which correspond uniquely to precise dLGN-V1 spike synchrony. These results provide evidence of a role for high gamma oscillations in mediating thalamocortical communication in the visual pathway of mice, analogous to beta oscillations in primates.

Born to Cry: A Genetic Dissection of Infant Vocalization.

Infant vocalizations are one of the most fundamental and innate forms of behavior throughout avian and mammalian orders. They have a critical role in motivating parental care and contribute significantly to fitness and reproductive success. Dysregulation of these vocalizations has been reported to predict risk of central nervous system pathologies such as hypoxia, meningitis, or autism spectrum disorder. Here, we have used the expanded BXD family of mice, and a diallel cross between DBA/2J and C57BL/6J parental strains, to begin the process of genetically dissecting the numerous facets of infant vocalizations. We calculate heritability, estimate the role of parent-of-origin effects, and identify novel quantitative trait loci (QTLs) that control ultrasonic vocalizations (USVs) on postnatal days 7, 8, and 9; a stage that closely matches human infants at birth. Heritability estimates for the number and frequency of calls are low, suggesting that these traits are under high selective pressure. In contrast, duration and amplitude of calls have higher heritabilities, indicating lower selection, or their importance for kin recognition. We find suggestive evidence that amplitude of infant calls is dependent on the maternal genotype, independent of shared genetic variants. Finally, we identify two loci on Chrs 2 and 14 influencing call frequency, and a third locus on Chr 8 influencing the amplitude of vocalizations. All three loci contain strong candidate genes that merit further analysis. Understanding the genetic control of infant vocalizations is not just important for understanding the evolution of parent-offspring interactions, but also in understanding the earliest innate behaviors, the development of parent-offspring relations, and the early identification of behavioral abnormalities.

Shaping Diversity Into the Brain's Form and Function.

The brain contains a large diversity of unique cell types that use specific genetic programs to control development and instruct the intricate wiring of sensory, motor, and cognitive brain regions. In addition to their cellular diversity and specialized connectivity maps, each region's dedicated function is also expressed in their characteristic gross external morphologies. The folds on the surface of the cerebral cortex and cerebellum are classic examples. But, to what extent does structure relate to function and at what spatial scale? We discuss the mechanisms that sculpt functional brain maps and external morphologies. We also contrast the cryptic structural defects in conditions such as autism spectrum disorders to the overt microcephaly after Zika infections, taking into consideration that both diseases disrupt proper cognitive development. The data indicate that dynamic processes shape all brain areas to fit into jigsaw-like patterns. The patterns in each region reflect circuit connectivity, which ultimately supports local signal processing and accomplishes multi-areal integration of information processing to optimize brain functions.